Synthesis of functionalized lactones: catalytic cross-coupling of 1,2-diols and allylic alcohols

Abstract

Simple industrial feedstock chemicals such as allylic alcohols and 1,2-diols are cross-coupled to deliver δ-hydroxybutyrolactones. The reaction occurs through O–H bond activation via amine–amide metal–ligand cooperation involving allylic aldehydes, radical intermediates, and Ru(III) species, as established by EPR studies. This tandem process proceeds with the liberation of molecular hydrogen as the only green byproduct.

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Lactones or cyclic esters are some of the fundamental functionalities in organic chemistry, are prevalently present in nature, and have widespread applications in chemical synthesis.¹ Lactones possess important biological properties and are extensively used in the perfume and food industries.² Lactones also serve as key intermediates in the synthesis of several natural products such as migrastatin, isomigrastatin, dorrigocin, and incrustoporin and its analogues.³ Notably, the butyrolactone core is present in clinically used FDA-approved drugs. For example, Pilocarpine® is an agonist used as a supplement in the treatment of glaucoma.⁴ A phthalide-based butyrolactone core bearing a hydroxy group shows anti-inflammatory activity and inhibits the NF-kB signaling pathway.⁵ Hence, the development of efficient strategies for the synthesis of valuable lactone scaffolds directly from simple, bio-renewable and readily available precursors is of prime interest. Numerous synthetic methods have been devised for the synthesis of diverse lactones.^5,6 The enzyme- or acid-catalysed cyclization of hydroxyacids is a common method for the synthesis of lactones (Scheme 1a).⁷ Dong developed an intramolecular ketone hydroacylation process catalysed by Noyori's asymmetric transfer hydrogenation catalyst for the enantioselective synthesis of lactones (Scheme 1b).⁸ The synthesis of γ-butyrolactones from diols and malonate esters using a Ru-MACHO-BH catalyst (Scheme 1c) was reported by Beller and co-workers.⁹ Our group has developed valuable synthetic methods involving borrowing hydrogen (BH)¹⁰ and acceptorless dehydrogenative coupling (ADC)¹¹ pathways employing the Ru-MACHO catalyst. Inspired by the previous reports and in continuation of our quest to develop synthetic methods using readily available feedstocks, herein, we report the unprecedented catalytic cross-coupling of 1,2-diols and allylic alcohols, leading to the synthesis of δ-hydroxybutyrolactones (Scheme 1d).

Scheme 1 Strategies towards the synthesis of butyrolactones.

Using the established optimized conditions (Table S1, see ESI†), the synthetic scope for the hydroxyl-functionalized butyrolactones was explored using different allylic alcohols and 1,2-diols with Ru-macho 1 as the catalyst. First, 1-phenylethane-1,2-diol was employed as the diol, and the reaction was carried out with diverse allylic alcohols (Table 1). Cinnamyl alcohols having electron-donating substituents such as alkyl, alkoxy, 3,4-dimethoxy and 3,4-methylenedioxy groups tolerated the reaction well, giving the corresponding lactones 3–7 in moderate-to-good yields. A cinnamyl alcohol having both electron-withdrawing and electron-donating substituents was also reacted under the optimized conditions, and delivered the corresponding lactone 8 in 67% isolated yield. Cinnamyl alcohols with electron-withdrawing groups such as 4-trifluoromethyl and 4-mesylate afforded the hydroxy lactones 9 and 10 in 72% and 63% yields, respectively. Pyrene- and thiophene-substituted allylic alcohols also underwent the catalytic coupling reaction with 1,2-diols and delivered the corresponding lactones 11 and 12 in moderate yields. The reaction of unactivated and challenging aliphatic allylic alcohols such as crotyl alcohol and 2-octen-1-ol with 1-phenylethane-1,2-diol resulted in the corresponding 4-methyl- and 4-pentyl-substituted butyrolactones 13 and 14, respectively. After the exploration of different allylic alcohols, the scope of 1,2-diols in the catalytic synthesis of δ-hydroxybutyrolactones was investigated. 4-Methyl-, 4-cyclohexyl- and 4-fluoro-substituted 1-phenylethane-1,2-diol derivatives afforded the desired products 15–17 in yields of 67–78%. When 1-naphthalene-1,2-ethanediol was reacted with simple cinnamyl alcohol, the corresponding lactone 18 was isolated in 64% yield. Diols bearing sensitive functional groups (ester, cyano and bromo) and reactive heteroarenes (furan, thiophene, and pyridine) were tested under the standard conditions, and among them, only the pyridine-substituted diol provided the hydroxy butyrolactone 19 in 45% yield. Ethyl- to hexyl-substituted linear aliphatic 1,2-diols were reacted, which afforded the corresponding lactones 20–23 in moderate yields. All the products were isolated as a mixture of diastereomers. The structure of the δ-hydroxybutyrolactones was unequivocally corroborated by the single-crystal X-ray analyses of products 2 (ref. 12) and 11.

Table 1 Substrate scope for catalytic synthesis of δ-hydroxybutyrolactones^a

a Reaction conditions: 1,2-diol (0.5 mmol, 1 equiv.), allylic alcohol (0.5 mmol, 1 equiv.), ^tamyl alcohol (2 mL), catalyst 1 (1 mol%), and NaOH (50 mol%) were heated at 100 °C under a nitrogen flow for 36 h. Reported yields were calculated for pure isolated products after column chromatography. b Reaction was performed using 2 equiv. of 1,2-diol.

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Further experiments were performed to understand the mechanistic pathways of the ruthenium-catalysed coupling of allylic alcohols and 1,2-diols. The dehydrohalogenation of catalyst 1 upon reaction with a base and the O–H activation of alcohols via an in situ formed coordinatively unsaturated Ru(II) intermediate have been established.¹³ The catalytic dehydrogenation of alcohol functionalities and in situ formation of carbonyl intermediates are anticipated during the reaction.^10,11 Thus, the reaction of 1-phenylethane-1,2-diol with cinnamyl aldehyde was carried out under the optimized conditions, which provided the hydroxy lactone 2 in 52% yield (Scheme 2a). A similar reaction in the absence of a catalyst produced no product. The reaction of α-hydroxyacetophenone with cinnamyl alcohol under the optimized conditions, as well as in the absence of a catalyst, failed to deliver the desired lactone product (Scheme 2b). These experiments confirm the necessity of catalyst 1 and indicate the involvement of an aldehyde intermediate in the reaction. Despite the absence of reaction, the formation of a carbonyl intermediate from 1,2-diols during the reaction cannot be ruled out, as the carbonyl compounds are known to undergo cycloadduct formation with coordinatively unsaturated intermediates, which can be detrimental to the catalysis.¹⁴ Next, the intermolecular formation of esters from allylic alcohols and 1,2-diols and subsequent intramolecular cyclization was envisaged.

Scheme 2 Mechanistic studies and control experiments on the catalytic cross-coupling of allylic alcohols with 1,2-diols.

Thus, cinnamyl ester 24 was prepared and subjected to reaction under the optimized conditions and in the absence of a catalyst (Scheme 2c). Both experiments failed to provide the desired lactone product. When phenylglyoxal hydrate was reacted with cinnamyl alcohol or cinnamaldehyde with or without catalyst 1, the formation of the desired lactone product 2 was not observed (Scheme 2d). Notably, when 3-buten-1-ol was reacted with 1-phenylethane-1,2-diol, the desired cross-coupling product 13 was isolated in 41% yield (Scheme 2e). Presumably, catalytic isomerization of the alkene functionality in situ generated the allylic alcohol from the homo-allylic alcohol, and subsequent catalytic cross-coupling resulted in lactone formation. Catalytic reactions performed in the presence of Hg (300 equiv. with respect to catalyst 1) and 1,10-phenanthroline (10 equiv. with respect to catalyst 1) delivered lactone 2 in 56% and 69% yields, respectively, indicating that the reactions proceed via molecular intermediates following homogeneous pathways (Scheme 2f). A deuterium-labelling experiment was performed with cinnamyl alcohol and deuterated 1-phenylethane-1,2-diol-d₅, and the result implied that the reaction proceeded via a hydrogen borrowing pathway (Scheme 2g). Product 2-d₄ was isolated in 71% yield, and exhibited 91% deuterium incorporation at the α-position, 19% at the β-position, and 44% at the γ-position of the hydroxyl group. A radical trapping experiment was performed using 1-phenylethane-1,2-diol, cinnamyl alcohol, catalyst 1 and base in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger (Scheme 2h). The reaction was interrupted at 4 h and subjected to mass analysis, which revealed the formation of radical intermediate V (ESI mass m/z 133.8952 amu, see Scheme 3).

Scheme 3 Proposed catalytic cycle.

On the basis of the mechanistic studies, a plausible mechanism for the catalytic cross-coupling of allylic alcohols and 1,2-diols is delineated in Scheme 3. Catalyst 1 undergoes dehydrohalogenation upon reaction with base, resulting in coordinatively unsaturated intermediate I.¹³ Reaction of intermediate I with allylic alcohol leads to an O–H activation via metal–ligand cooperation and the formation of alkoxy-ligated ruthenium intermediate II (observed from the ³¹P NMR spectrum of the stoichiometric reaction between 1 and cinnamyl alcohol, which revealed a characteristic signal at δ 55.34 ppm, see Fig. S2, ESI†). Further, the allylic aldehyde is liberated from II (perhaps via β-hydride elimination), resulting in ruthenium dihydride III. The in situ formed allylic aldehyde reacts with intermediate I and base to generate the radical alkoxy-ligated Ru(III) intermediate IV. EPR analyses of the independent reaction of catalyst 1 with base and allylic alcohol indicated the involvement of radical species IV in 40(3)% (see Fig. S6, ESI†). Allylic radical isomerization and dissociation from metal center lead to benzylic radical intermediate V and the regeneration of I. Simultaneously, the 1,2-diol reacts with intermediate I, leading to the selective activation of the primary hydroxy group (as inferred from ³¹P NMR spectroscopy of the stoichiometric reaction between catalyst 1, base, 1,2-diol and a secondary alcohol, see Fig. S3 and S4, ESI†), which suggested the eventual generation of radical Ru(III) intermediate VI; however, the presence of Ru(III) species was not observed in the catalytic reaction mixture, which can be attributed to concomitant reduction of Ru(III) to an EPR-inactive Ru(II) intermediate and an organic radical (Fig. 1b). In contrast, the presence of an EPR-active low-spin Ru(III) intermediate (S = 1/2) was observed (45(5)%) in the independent reaction of catalyst 1, base and 1,2-diol (Fig. 1a). The produced organic radical and low-spin Ru(III) possess a spin state of S = 1/2; therefore, the galvinoxyl radical (S = 1/2) was used as a reference compound to determine the spin amount (see Fig. S7, ESI†). The reaction of VI with alcohol regenerates the active intermediate I and generates the radical VII.

Fig. 1 EPR spectra (a) recorded for the reaction of catalyst 1, base and 1,2-diol, and (b) for the reaction of catalyst 1, base, 1,2-diol and allylic alcohol.

The formation of a C−C bond via the radical combination of intermediates V and VII provides the intermediate VIII. Base-mediated intramolecular nucleophilic attack of the γ-hydroxyl group with the aldehyde functionality results in the formation of intermediate IX. The activated hemiacetal functionality in IX is dehydrogenated by intermediate Ivia O–H activation (X), which delivers the hydroxylactone product and III. Overall, two equivalents of intermediate III are generated in the reaction via the oxidation of alcohol motifs, which liberates two equivalents of molecular hydrogen and regenerates intermediate I. The base-promoted radical formation and amine–amide metal–ligand cooperation operative in the catalyst facilitated this tandem process, resulting in successful and efficient coupling of allylic alcohols and 1,2-diols. Furthermore, a radical peak was observed in the EPR analysis for the reaction of catalyst 1, base, 1,2-diol and allylic alcohol (Fig. 1b).

In summary, the synthesis of δ-hydroxybutyrolactones was attained via the coupling of two simple feedstock chemicals, 1,2-diols and allylic alcohols. The reaction was catalysed by a commercially available ruthenium pincer catalyst with minimal catalyst loading. Upon activation by base, the catalyst oxidized both 1,2-diols and allylic alcohols via radical pathways, resulting in a cross-coupling reaction. The involvement of radical intermediates was established through EPR studies. Two equivalents of liberated molecular hydrogen are the only byproducts. This simple yet effective synthesis of valuable δ-hydroxybutyrolactones from readily available feedstocks will advance the sustainability of chemical synthesis.

P. M. and R. V. S. thank DAE for the Fellowship. M. S. thanks SERB New Delhi (CRG/2023/002850) for the financial support. C. G. thanks SERB New Delhi (CRG/2021/001706), DAE, and NISER for financial support.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data of product 11 has been deposited at the CCDC under 2348651.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2348651. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5cc02207j

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